Impact of previous M184V on virological outcome of switch to 3TC-based dual therapies Poster 4981Institute of Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy; 2Infectious Diseases Unit, Siena University Hospital, Siena, Italy; 3Division of Infectious Diseases, ASST Papa Giovanni XXIII, Bergamo, Italy: 4Clinic of Infectious and Tropical Diseases, Azienda Ospedaliera Universitaria Careggi, Firenze, Italy: 5Clinica Malattie Infettive

e Tropicali, Azienda Ospedaliero Universitaria di Modena, Modena, Italy; 6Microbiology and Virology Unit, Azienda Ospedaliero Universitaria di Modena, Modena, Italy; 7Infectious Diseases, IRCCS AOU San Martino-IST, Genova, Italy; 8Microbiology and Virology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy; 9Hygiene Unit, IRCCS AOU San Martino-IST, Genova, Italy; 10Department of Medical Biotechnologies, University of Siena, Siena, Italy; 11Virologia Molecolare, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 12Infectious Diseases Clinic, S. Matteo Hospital, Pavia, Italy.

Gagliardini R1,2, Ciccullo A1 , Borghetti A1 , Maggiolo F3 , Bartolozzi D4 , Borghi V5 , Pecorari M6 , Di Biagio A7 , Callegaro A8 , Bruzzone B9 , Saladini F10 , Paolucci S11 , Bellazzi L12 , Di Giambenedetto S1 , De Luca A2

• M184V:• reduces susceptibility to lamivudine• reduces HIV replication capacity

• Dual therapies (DT) are largely prescribed as simplification strategies inEuropean countries:

• DHHS guidelines: PI/r + 3TC (BI)• EACS guidelines: 3TC + DRVr/c c + LPV/r or + ATV/r/c• PI/r + 3TC (ATLAS-M, SALT, OLE) versus triple therapy: overall RR of

virological failure 0.77• DTG+ 3TC (LAMIDOL): highly effective

• ANRS12286/Mobidip trial showed high efficacy of PI/r+3TC versus 2NRTI+PI/ras switch in virosuppressed on 2nd line, despite the presence of M184V atbaseline.

• A direct comparison of efficacy of 3TC containing DT with or without of M184Vhas not been performed.

• Aim of the study was to compare virological efficacy of bPI or INI +3TC inpatients with and without a history of M184V detection.

Introduction

§ Retrospective observational study performed in the ARCA database

§ Pts with HIV-RNA ≤50 cps/mL switching to DT (3TC+ PI/r or INI) and with atleast one previous genotype were selected

§ Primary endpoint:

§ Time to virological failure in M184V+ and M184V-

§ Secondary endpoints:

§ Predictors of virological failure and virological blips

§ Time to virological blips in M184V+ and M184V-

§ Definitions:

§ Virological failure (VF): 2 VL >50 cp/mL or single value ≥200 cp/mL

§ Viral blip (VB): single VL 51-199 cp/mL, not confirmed

§ M184V was assessed in the historical genotypic resistance tests (hGRT) andin the last genotype

§ Genotypic sensitivity score (GSS) was calculated on the hGRT according tothe AntiRetroScan 2.0 genotypic interpretation system (www.dbarca.net)

§ Statistical analysis:

§ Student-t and Chi Square tests employed to evaluate the differences between groups at baseline, as appropriate

§ Kaplan-Meier curves to analyze time to VF and to VB

§ Cox proportional hazards regression analysis to analyze the risk factors associated to VF and VB

Methods

M184V- (n=349) M184V+ (n=87) p

Age, years* 46 (39; 53) 52 (48; 57) <0.001

Male sex 257 (72%) 53 (61%) 0.019

Caucasians 308 (88%) 84 (97%) 0.077

Risk factorSexualIDUOther/unknown

225 (64%)40 (11%)84 (24%)

56 (64%)21 (24%)10 (11%)

0.001

HCV infection 62 (18%) 24 (28%) <0.001

HBsAg+ 12 (3%) 2 (2%) 0.001

Previous AIDS events 40 (12%) 16 (18%) 0.084

HIV-RNA at zenith, cps/mL* 104,750(35,807;329,250)

107,910(27,000;252,900)

0.416

Years from HIV diagnosis* 7.8(3.8;13.7) 19.2 (16.1;23.0) <0.001

Years from first ART initiation * 5.6 (2.8;10.0) 16.6 (12.8;18.9) <0.001

Duration of viral suppression,years*

3.8 (2.2;6.4) 6.6 (3.7;8.9) <0.001

Nadir CD4+, cells/µL* 224 (81;313) 147 (57;199) <0.001

Current CD4+, cells/µL* 620 (453;780) 632 (409; 922) 0.131

Type of DT:lamivudine+bPIlamivudine+INI

242 (69%)107 (31%)

64 (74%)23 (26%)

0.441

Calendar year* 2014 (2013; 2015) 2014 (2012; 2015) 0.121

GSS of the 2nd drug ** 0.99 (0.07) 0.91 (0.20) <0.001Data are shown as n (%); * median (IQR), ** mean (SD).Notes: IDU, injecting drug users; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; ART,antiretroviral therapy; BL, baseline; DT, dual therapy; lamivudine; bPI, boosted protease inhibitors; INI,integrase inhibitor; GSS, genotypic sensitivity score.

Notes: 3TC, lamivudine; LPV,lopinavir; r, ritonavir; ATV, atazanavir;DRV, darunavir; DTG, dolutegravir;RAL, raltegravir.

Notes: PI, protease inhibitors; INI, integraseinhibitor; NRTI, nucleoside reverse-transcriptaseinhibitors;NNRTI, non- nucleoside reverse-transcriptaseinhibitors; DT, dual therapy

Table 1: patients baseline characteristics

Patients baseline characteristics436 pts were included: 87 had the M184V mutation at the hGRT (M184V+).The M184V+ group more frequently included females, IDU, had older age,lower CD4+ at nadir, longer duration of ART and of viral suppression. Patientsbaseline characteristics are shown in Table 1 and in Figure 1a and 1b.

Results

Incidence of virological failure during 693 person-years offollow-up (PYFU):

- 5.1 per 100 PYFU in M184V+

- 3.1 per 100 PYFU in M184V-

Virological failures were

- in the M184V+ group: 4 on 3TC+atazanavir/r and 3 on3TC+darunavir/r;

- in the M184V- group: 7 on 3TC+atazanavir/r, 5 on3TC+darunavir/r, 3 on 3TC+lopinavir/r and 2 on3TC+dolutegravir.

Time to VF did not differ between M184V+ and M184V-(Figure 2) and predictors of VF were the zenith VL valueand HBsAg positivity (Table 2).

1b

To minimize the difference in duration of viral

suppression prior to baseline between the groups, an

analysis selecting patients with viral suppression ≤6.6

years (the median duration of viral suppression in the

M184V+ group) was performed (n=308).

The 3-year probability of remaining free from VF were

82.9% (95% CI 67.2; 98.6) in the M184V+ group and

92.5% (95% CI 86.8; 98.2) in the M184V- group

(p=0.080) (Figure 3).

In this subset, zenith VL was the only predictor of VF.

3-year probability of remaining VF-free:M184V+: 87.8% (95% CI 78.4;97.2) M184V-: 91.9% (95% CI 86.6;97.2)

log rank p=0.323

At a sensitivity analysis, where

M184V detection was based on the

last available genotypic resistance

test (n=85 M184V+patients), 3-year

probability of remaining free from

VF was:

- M184V+: 87.8% (95% CI 78.4;

97.2);

- M184-: 91.9% (95% CI 86.6;

97.2), log rank p=0.316.

3-year probability of remaining free from VBM184V+: 79.8% (95% CI 67.8; 91.8) M184V-: 90.1% (95%CI 84.0; 96.2)

log rank p=0.016

Discussion and conclusions

Prior selection of M184V did not seem to play asignificant role on virological efficacy with3TC+bPI or DTG as switch regimens.Nonetheless a virological signal was observedwith M184V+ patients showing a higherprobability of VB and shorter time of prior viralsuppression appearing to increase the risk of VFand of VB in this group. However, duration of viralsuppression was not a predictor of VF or VB.Limitations of the study: retrospective design,limited statistical power, no data aboutadherence, different characteristics of the twogroups at BL.

Hypothesis/explanation:• decreased viral fitness does not allow viral

rebound;• protective role of M184V against the selection

of dolutegravir resistance mutations (no failuredetected in n=21 patients on 3TC+DTGfollowed a median of 10 months [IQR 6; 14]);

• longer duration of viral suppression coulddisproportionally reduce the size of thereservoir of replication-impaired viruses suchas M184V-carrying viral variants.

1a

Viral blips occurred in 10 of 80 (13%) M184V+ patients during 112 PYFU and 18 of 332 (5%) M184V- patients during 502 PYFU. Time to VB is shown in figure 4 andpredictors in Table 3. In the subset of patients with viral suppression ≤6.6 years, viral blips were 13/52 in M184V- and 8/37 in M184V+ and the difference in the 3-yearprobability of remaining free of blips was even larger (figure 5).

3-year probability of remaining free from VBM184V+: 69.4% (95% CI 50.6; 88.2) M184V-: 91.1% (95% CI 84.8;97.4)

log rank p<0.001

AcknowledgmentARCA group: Vincenzo Mellace [CATANZARO - SERT Soverato]; Amedeo Capetti [MILANO - Prima Divisione Malattie Infettive Ospedale L. Sacco];Maria Rita Gismondo [MILANO - Laboratorio Microbiologia Ospedale L. Sacco (Dipart. Scienze Cliniche, Sez. Malattie Infettive)]; Maria Luisa Biondi[MILANO - Laboratorio di diagnostica molecolare infettivologica AO S. Paolo]; Cristina Mussini [MODENA - Clinica Malattie Infettive]; Monica Pecorari[MODENA - Virologia]; Nicola Gianotti [HSR - Studio MUSA]; Daria Sacchini [PIACENZA - Malattie Infettive]; Giustino Parruti [PESCARA - MalattieInfettive]; Ennio Polilli [PESCARA - Virologia Pescara]; Franco Baldelli [PERUGIA - Malattie Infettive]; Stefania Zanussi [AVIANO - Centro diRiferimento Oncologico]; Alessandro Nerli [PRATO - Malattie Infettive]; Lucia Lenzi [PRATO - Virologia]; Carlo Calzetti [PARMA - Divisione Malattie

Infettive ed Epatologia Azienda Ospedaliera]; Angela Vivarelli [PISTOIA - Malattie Infettive]; Renato Maserati [PAVIA - Ambulatorio Clinica MalattieInfettive S. Matteo]; Fausto Baldanti [PAVIA - Virologia S. Matteo]; Federica Poletti [VERBANIA - Malattie Infettive VERBANIA]; Vincenzo Mondino[VERBANIA - Virologia]; Marina Malena [VERONA - Centro di Medicina Preventiva-ULSS 20]; Antonio Cascio [PALERMO - Malattie Infettive Policlinico"P. Giaccone"]; Gaetano Filice [PAVIA - Clinica Malattie Infettive e Tropicali]; Giacomo Magnani [REGGIO EMILIA - Malattie Infettive]; AlessandroZerbini [REGGIO EMILIA - S.S Autoimmunità, Allergologia e Biotecnologie Innovative]; Francesca Lombardi [ROMA - Laboratorio virologia Cattolica];Simona Di Gaimbenedetto [ROMA - Istituto di Clinica Malattie Infettive Cattolica]; Massimo Andreoni [ROMA - Cattedra Malattie Infettive Tor Vergata];Marco Montano [ROMA - Virologia per Malattie Infettive Tor Vergata]; Vincenzo Vullo [ROMA - Malattie Infettive e Tropicali La Sapienza - Umberto I];

Ombretta Turriziani [ROMA - Medicina Sperimentale e Patologia - Sezione Virologia - La Sapienza]; Maurizio Zazzi [SIENA - Virologia]; AngelaGonnelli [SIENA - Malattie Infettive]; Andrea De Luca [SIENA - Malattie Infettive 2]; Enzo Boeri [MILANO - Virologia HSR]; Stefano Bonora [TORINO -Malattie Infettive Amedeo di Savoia]; Valeria Ghisetti [TORINO - Laboratorio di Virologia, Ospedale Amedeo di Savoia]; Daniela Francisci [TERNI -Malattie Infettive]; Paolo Grossi [VARESE - Clinica Malattie Infettive e Tropicali]; Patrizia Bagnarelli [ANCONA - Virologia]; Luca Butini [ANCONA -Immunologia Clinica]; Romana del Gobbo [ANCONA - Malattie Infettive]; Andrea Giacometti [ANCONA - Clinica di Malattie Infettive]; Danilo Tacconi[AREZZO - Malattie Infettive]; Laura Monno [BARI - Clinica Malattie Infettive Università]; Grazia Punzi [BARI - Virologia]; Annapaola Callegaro[BERGAMO - Microbiologia e Virologia]; Franco Maggiolo [BERGAMO - Malattie Infettive]; Alessia Zoncada [CREMONA - Malattie Infettive]; Elisabetta

Paolini [CREMONA - Servizio Immunoematologia e Medcina Trasfusionale]; Laura Sighinolfi [FERRARA - Malattie Infettive AOU S. Anna]; GraziaColao [FIRENZE - Virologia CAREGGI]; Paola Corsi [FIRENZE - Malattie Infettive CAREGGI]; Pierluigi Blanc [FIRENZE - Malattie Infettive SMAnnunziata]; Luisa Galli [FIRENZE - Malattie Infettive Pediatria Meyer]; Paola Meraviglia [MILANO - Seconda Divisione Malattie Infettive Ospedale L.Sacco]; Andrea Tosti [FOLIGNO - Malattie Infettive / SERT]; Bianca Bruzzone [GENOVA - Laboratorio di Igiene Ospedale S. Martino]; Maurizio Setti[GENOVA - Clinica Medica Immunologia]; Giovanni Penco [GENOVA - Malattie Infettive Ospedali Galliera]; Antonio Di Biagio [GENOVA - MalattieInfettive Ospedale S. Martino]; Cesira Nencioni [GROSSETO - Malattie Infettive]; Riccardo Pardelli [LIVORNO - Malattie Infettive]; Irene Arcidiacono[LODI - Malattie Infettive]; Alberto Degiuli [LODI - Virologia Lodi]; Michele De Gennaro [LUCCA - Malattie Infettive]; Alessandro Soria [MONZA -

Malattie Infettive]; Alfredo Focà [CATANZARO - U.O. di Microbiologia Clinica]; Surace/Latella [CATANZARO - Centro Mallattie Epatiche e Trapianti];Lucio Cosco [CATANZARO - U.O. Malattie Infettive Ospedale Pugliese Ciaccio]; Sergio Malandrin [MONZA - UO Microbiologia AO S. Gerardo]; PaolaMilini [MACERATA - Malattie Infettive]; Paola Cicconi [MILANO - Clinica di Malattie Infettive Ospedale S. Paolo]; Stefano Rusconi [MILANO - Dipart.Scienze Cliniche, Sez. Malattie Infettive - Università degli Studi]; Valeria Micheli [MILANO - Laboratorio Microbiologia Ospedale L. Sacco (SecondaDivisione Malattie Infettive)]

Univariate analysis Multivariable analysis 1 Multivariable analysis 2Variables HR (95% CI) p value aHR (95% CI) p value aHR (95% CI) p valueM184V in hGRT 1.56 (0.64;3.76) 0.327 1.23 (0.46;3.31) 0.684 1-11 (0.38; 3.23) 0.847

Type of DT (PI vs INI) 0.42 (0.10;1.85) 0.251

Age (+ 10 years) 1.17 (0.83;1.65) 0.381 1.11 (0.73; 1.69) 0.625

Gender (male vs female) 0.66 (0.29;1.50) 0.320 0.61 (0.25; 1.51) 0.284

Ethnicity (Caucasian vs other) 0.60 (0.14; 2.54) 0.483

Risk factor (ref. sexual)IDUOther/unknown

2.40 (0.85; 6.75)1.51 (0.57; 4.02)

0.0980.411

HCV infection (ref. absent)presentUnknown

1.85 (0.78; 4.37)0.16 (0.02; 1.19)

0.1630.073

HBsAg (ref. negative)PositiveUnknown

8.85 (2.25; 31.5)0.50 (0.15; 1.71)

0.0010.269

12.53 (2.15; 72.96)1.67 (0.46; 5.96)

0.0050.437

Previous AIDS-defining events 1.34 (0.46: 3.93) 0.594

Time from first ART initiation (+ 1year)

1.07 (1.01;1.13) 0.032

Duration of virological suppressionbefore baseline (+ 1 year)

0.97 (0.86; 1.16) 0.965 0.95 (0.81;1.1) 0.949 0.92 (0.79;1.08) 0.306

Baseline CD4+ counts (+100 cells/µl) 0.99 (0.86;1.14) 0.922

Nadir CD4+ counts (+100 cells/µl) 0.86 (0.64; 1.16) 0.319

Zenith HIV-RNA (+1 log10 copies/mL) 1.91 (1.06; 3.42) 0.030 1.91 (1.05; 3.49) 0.035 1.61 (0.89; 2.91) 0.116

GSS of the 2nd drug (+0.5) 0.36 (0.16; 0.84) 0.018 0.41 (0.16; 1.03) 0.058 0.41 (0.15;1.19) 0.082

Table 2: predictors of virological failure

Note: HR, hazard ratio; aHR, adjusted hazard ratio; hGRT, historical genotype resistance test; DT, dual therapy; PI, protease

inhibitors; INI, integrase inhibitor, IDU, injective drug users; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; ART,

antiretroviral therapy; GSS, genotypic sensitivity score.

Univariate analysis Multivariable analysisVariables HR (95% CI) p value aHR (95% CI) p value

M184V in hGRT 2.51 (1.15;5.44) 0.020 2.45 (1.09; 5.53) 0.030

Type of DT (PI vs INI) 0.56 (0.19;1.63) 0.284

Age (+ 10 years)Gender (male vs female) 1.79 (0.68; 4.70) 0.241

Ethnicity (Caucasian vs other) 1.38 (0.18;10.20) 0.751

Risk factor (ref. sexual)IDU

Other/unknown1.57 (0.53; 4.68)1.20 (0.54; 3.14)

0.4200.558

HCV infection (ref. absent)PresentUnknown

2.89 (1.21; 6.87)1.28 (0.50;3.25)

0.0170.607

2.71 (1.14; 6.48)1.57 (0.60; 4.09)

0.0250.361

HBsAg (ref. negative)PositiveUnknown

0.00 (0.00;0.01)1.17 (0.50;2.75)

0.9750.725

Previous AIDS-defining events 1.08 (0.38; 3.13) 0.883

Time from first ART initiation (+ 1 year) 1.04 (0.98;1.10) 0.188

Time of virological suppression (+ 1 year) 1.02 (0.90; 1.16) 0.753

Baseline CD4+ (+100 cells/µl) 1.07 (0.95; 1.21) 0.233

Nadir CD4+ (+100 cells/µl) 0.95 (0.73; 1.22) 0.671

Log zenith HIV-RNA 1.10 (0.66;1.82) 0.721

GSS of the 2nd drug (+ 0.5) 0.29 (0.08;1.56) 0.113

Table 3: predictors of viral blipsFigure 1: dual therapies started at BL (1a) and previous ART regimens (1b)

Virological outcomes

Note: HR, hazard ratio; aHR, adjuster hazard ratio; hGRT, historical genotype resistance test; DT, dual

therapy; PI, protease inhibitors; INI, integrase inhibitor, IDU, injective drug users; HCV, hepatitis C

virus; HBsAg, hepatitis B surface antigen; ART, antiretroviral therapy; GSS, genotypic sensitivity score.

Figure 2: estimated probability of remaining free from VF according to previous M184V detection

Years from treatment initiation

Years from treatment initiation

Years from treatment initiation

Pro

porti

onof

pts

free

from

VF

Years from treatment initiation

Pro

porti

onof

pts

free

from

VF

Pro

porti

onof

pts

free

from

VB

Figure 3: estimated probability of remaining free from VF in dual therapy for different time of viral suppression

Pro

porti

onof

pts

free

from

VB

Figure 5: estimated probability of remaining free from VB in patients with viral suppression ≤6.6 years

Figure 4: estimated probability of remaining free from viral blips

M184V-M184V+

M184V-M184V+

M184V-M184V+